Analysis of human colorectal cancer (CRC) and mouse models of CRC reveals decreased expression of
enzymes that mediate short chain fatty acid (SCFA) metabolism, including ACSS2. Unlike in many other cancers,
low ACSS2 expression is associated with CRC progression, and predicts poor disease-free survival. ACSS2
generates cytosolic and nuclear acetyl CoA from acetate for de novo lipid synthesis and drives locus-specific
histone acetylation to promote gene expression. Experimentally increasing ACSS2 in human CRC cells limits
clonogenicity and growth in soft agar, consistent with ACSS2 restraining tumorigenesis.
Colon tumors develop in a unique metabolic environment, in which gut bacteria generate high levels of
SCFAs, including acetate and butyrate. Normal colon epithelia rely on bacterial SCFAs, primarily butyrate, for
their energy needs. As with ACSS2, butyrate metabolic enzymes, including ACSM3 and ACADS, are
downregulated in CRC, and low expression correlates with poor survival. We show that increasing ACSM3
expression reduces proliferation in human CRC cell lines, and that mice with a spontaneous deletion of ACADS
are more susceptible to carcinogen induced colon adenomas. Thus, our preliminary data support a model in
which ACSS2 and butyrate metabolic enzymes limit tumorigenesis specifically in the colon.
Our overall hypothesis is that low ACSS2 expression promotes CRC via decreased histone acetylation
and expression of its target genes, including those that encode butyrate metabolism. This facilitates a switch
from SCFA metabolism to glycolysis in the tumor. However, it also creates a cancer-specific vulnerability,
whereby CRC cells with low ACSS2 are impaired in their ability generate acetyl CoA for histone acetylation and
de novo lipid synthesis. We propose to exploit this tumor-specific vulnerability therapeutically by targeting acetyl
CoA synthesis together with nuclear processes that depend on ACSS2-mediated histone acetylation.
Three Aims will address our overall hypothesis: 1) We will use mouse models, human CRC cell lines and
xenografts to test if ACSS2 and ACADS restrain both primary colon tumors and metastases. 2) We will test if
ACSS2 limits CRC by controlling locus-specific histone acetylation, and if ACSS2 drives butyrate metabolic gene
expression to increase butyrate use and inhibit glycolysis. 3) We will test the hypothesis that low ACSS2 levels
sensitize colon tumors to therapies targeting chromatin-templated functions that depend on ACSS2.
This work will elucidate a novel tumor restraint function for ACSS2 in CRC, determine how ACSS2
controls metabolism, and identify new therapeutic approaches for CRC.